A new study from Baylor College of Medicine may pave the way for a more personalized approach to treating estrogen receptor-positive (ER+) breast cancer, the most common form of the disease.
Researchers have identified a biomarker that could predict which tumors are more likely to respond to CDK4/6 inhibitors, a class of drugs often added to standard endocrine therapy. The findings, published in Science Translational Medicine, could guide future clinical trials and more targeted treatment strategies.
ER+ breast cancers depend on estrogen to grow and are typically treated with endocrine therapies that block the hormone’s effects. To prevent relapse, many patients also receive CDK4/6 inhibitors—such as abemaciclib and ribociclib—for up to three years.
However, not all patients benefit from these drugs, exposing some to prolonged treatment and potential side effects without clear clinical justification.
In preclinical models, the Baylor team found that roughly 20% of ER+ tumors show low levels of a tumor suppressor protein called neurofibromin, encoded by the NF1 gene. These tumors were less responsive to standard endocrine therapy but exhibited heightened sensitivity to CDK4/6 inhibitors.
The study, led by Drs. Ze-Yi Zheng, Anran Chen, Matthew Ellis, and Eric Chang at Baylor’s Lester and Sue Smith Breast Center, was inspired by clinical data showing that NF1-deficient tumors have unusually high CDK4/6 activity, indicating potential drug susceptibility.
“Molecular data from patient samples can guide lab research in important new directions,” said Chang, a professor at the Breast Center and member of Baylor’s Dan L. Duncan Comprehensive Cancer Center.
Preclinical experiments combining a CDK4/6 inhibitor with the estrogen blocker fulvestrant produced durable tumor regressions in patient-derived xenograft (PDX) models. These results were further supported by analysis of serial patient biopsy samples treated with an aromatase inhibitor alone, followed by addition of palbociclib, another CDK4/6 inhibitor.
Ellis emphasized the next steps: “More clinical studies are needed to validate our findings. A major challenge has been developing a reliable test to measure NF1 levels in patient samples so confirmatory trials can move forward.” To address this, Chang’s lab developed immunohistochemistry- and mass spectrometry-based assays that quantify NF1 protein, offering a potential tool to identify patients most likely to benefit from CDK4/6 inhibitors.
The study was funded by grants from the National Institutes of Health, the Department of Defense, and the Cancer Prevention & Research Institute of Texas.
